High-density lipoprotein as a source of cholesterol for adrenal steroidogenesis; a study in individuals with low plasma HDL-C.

Bochem AE, Holleboom AG, Romijn JA et al.
J Lipid Res. 2013 Apr 22

Background

The adrenal glands can synthesize cholesterol, metabolise intracellular esterified cholesterol or obtain cholesterol from circulating lipoproteins. This cholesterol can then be used to synthesise and secrete adrenal steroid hormones.  Little is known about to what extent plasma lipoprotein levels contribute to adrenal steroidogenesis. Evidence suggests that LDL-C does not play a major role in delivering cholesterol for steroid hormone production [1-3]. HDL-C however may do, as low HDL-C levels were associated with decreased adrenal responses to synthetic ACTH in critically ill patients [4]. Experimental studies in mice also suggest that HDL is an important cholesterol donor [5-7]. In mice and humans, impaired cholesterol uptake from HDL through the scavenger receptor type B1 (SRB1) leads to compromised adrenal function [8-10]. The role of plasma HDL-C levels in relation to adrenal steroidogenesis in humans is still unclear.
Therefore, basal and ACTH-stimulated adrenal cortical function was assessed in males with low HDL-C due to mutations in either ATP-binding cassette transporter 1 (ABCA1, 24 carriers included) or lecithin-cholesterol acyltransferase (LCAT , 40 carriers) and in subjects with low HDL-C without mutations in ABCA1/LCAT (n=11), as well as in normolipidemic controls.

Main results

• Lower 24-hour excretion of 17-ketogenic steroids (17-KS) was detected in ABCA1 mutation carriers (33%, P=0.003), in LCAT mutation carriers (27%, P=0.01) and in the low HDL-C group (30%, P=0.04), as compared to controls. These differences remained statistically significant after correcting for differences in plasma LDL-C and statin use.
• Free urinary cortisol did not differ between ABCA1 and LCAT mutation carriers and controls, and neither did plasma levels of ACTH.
• The cortisol response to physiological levels of ACTH can be measured in a cosyntropin stimulation test, as a means to assess adrenal function. The peak serum cortisol response to ACTH was comparable in ABCA1 and LCAT mutation carriers, and did not differ from controls.  Plasma lipid levels did not change as a result of the cosyntropin test.

Conclusion

Men with low levels of HDL-C (irrespective of molecular origin) showed lower urinary excretion of total 17-KS as compared to normolipidemic controls, indicative of disturbed basal corticosteroid synthesis. The response to ACTH was not altered by mutations in either ABCA1 or LCAT. These data suggest that the supply of plasma lipoprotein derived cholesterol is used for basal adrenal steroidogenesis, but that this pathway is not able to respond to acute stress.

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